Obsessive Compulsive Disorder (OCD) is a chronic psychiatric illness that affects from 2-3% of the worldwide population. It is estimated that 20% of OCD patients are refractory to available psychological and pharmacological treatments. While the pathophysiology of OCD remains incompletely understood, recent evidence indicates abnormalities in the medial and orbital frontal-basal ganglia circuit. Indeed, correction of hyperactivity in orbital frontal cortex (OFC) is a common factor across effective pharmacological, behavioral, and neurosurgical therapies. Furthermore, our pilot studies using deep brain stimulation (DBS) show that the most promising target for DBS for OCD is in the ventral anterior internal capsule (VC) and adjacent ventral striatum (VS). However, there are several afferent and efferent projections that course through and converge at this location that may modulate OFC activity. The goal of this grant is to delineate the neural network and physiology underlying the effects of deep brain stimulation (DBS) for obsessive compulsive disorder (OCD), using a series of integrated translational experiments that involve: 1. functional neuroimaging in humans (aim 1), 2. tract tracing in nonhuman primates (aim 2), and 3. electrophysiology in rodents (aim 3). We will focus on two competing hypotheses: 1. that DBS acts primarily via fibers directly connecting the OFC with the thalamus, and 2. that DBS indirectly modulates OFC activity primarily through its stimulation of the VS pathways. Furthermore, an additional goal of the experiments is to delineate other key structures and transmitters, most specifically dopamine, (DA); and serotonin, (5HT), that may be involved at different points of DBS in the VS. Aim 1 will test the hypothesis that acute electrical stimulation at the VC/VS target will affect activity in OFC, ACC and functionally related areas, including the striatum, globus pallidus, and thalamus. Aim 2 will test the hypothesis that different regions of the VC carry specific cortical circuits and those circuits will differ substantially from those activated in the VS. Aim 3 will determine which candidate pathway (direct, via the thalamus; or indirect, via the VS and ventral pallidum) activated during DBS primarily modulates OFC activity patterns. A better understanding of the underlying neural circuitry of psychiatric disorders is a key element for developing the next generation of effective treatments.